Ampk Agonists Exercise Mimetics Via Pgc1a Biology Essay

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It is well known to everybody that exercise which is a physical activity is important in maintaining and improving persons health and fitness [1]. Exercise regularly helps circulatory system to increase oxygen and nutrient to the body and take out waste products .It also maintains strong and healthy bones and muscle [2]. Physical activity helps people also in reducing feeling of depression because it produces a chemical substance called endorphins that makes you feel happy [1, 2]. Exercise can reduce your risk of heart disease and stroke [1, 2, 3].

Expert recommended that you should do 20 to 30 minutes of aerobics exercise, 3 or 6 times a week [2,3]. In 2006 a Health Survey in England data shown that, only 40% of men and 28% of women met the current guidelines of physical active, whereas one third of the people are inactive [4].

Health Survey for England data show that, in 2006, only 40% of men and 28% of women met the current physical activity guidelines [4], whereas around one third of English adults were inactive, that is, participated in less than one occasion of 30 minutes activity a week. In 2003 in Scotland, the percentage achieving the recommended level was higher than in England [4].

Butcher.L et.al agreed that regular exercise protects against al cases of mortality by protecting atherosclerosis and typeII diabetes, breast cancer and colon cancer [5].

Section 1.2 - Type 2 Diabetes and Atherosclerosis.

Type2 Diabetes:

Type 2 diabetic it is called non-insulin-dependent diabetes mellitus (NIDDM) characterise by high level of glucose in the blood. NIDDM is a metabolic disorder caused by a defect in insulin secretion, insulin action, or both. Causes of Type II diabetes is obesity, genetic, smoking and high blood pressure [3, 6]. Campbell.P et.al agreed that insulin resistance and damages of pancreatic B cells may cause type 2 diabetic mellitus. This may contribute to prothrombetic state and increase the risk of cardiovascular disease[6].

Atherosclerosis:

Atherosclerosis is a disease in which a plaque builds up in the blood arterial wall. The plaque is made up of macrophages, fat, cholesterol and calcium[7] .In the arterial wall the endothelial inflammatory response is mediated by macrophages and some subtypes of T-lymphocyte. These T-lymphocytes recognise antigen represented by activated macrophages and in response, it generates cytokines that amplify the inflammatory process[39]. In these response it doesn't remove or neutralise the offending agent, the process continues with eventual thicken of the arterial wall[7]. That will result in complete or partial blockage to the blood flow. In some cases the plaque can rupture causing arterial thrombosis. It is the primary cause of coronary artery disease and cerebrovascular disease [7]. There are many factor that may causes atherosclerosis includes, smoking, hyperlipidemias, high blood pressure and diabetes.

Section 1.3 - Exercise and Type 2 Diabetes/Atherosclerosis:

Regular exercise protect against all causes of mortality .Butcher.l, et.al say that there is substantial evidence that the oxidation of LDL enhance the atherogenic process[5]. Oxidised LDL can be increased by exercise which in its role will increase the activity of PPARγ in monocyte leading to induce the activity of its regulator gene that would result in increasing cellular uptake of lipids[5]. Butcher,L et.al hypothesise in the same study that low density of exercise promotes the clearness of proatherogenic lipids (cholesterol) including monocytes and macrophages from peripheral tissues via HDL-mediated transfer to the liver , that will affect the PPAR γ target genes such as leukocytes CD36 which is expressed in many cells that involves in atherosclerosis such as macrophages and monocytes[5] .

Exercise has a strong effect on type 2 diabetes, it is recommended in treating this patients[3]. Thomas .D, et.al 2007 found in a study that; exercise has significantly decreased glycolytic haemoglobin (HbA1c) levels, so that's improved glycaemic control in people with this disease[8]. It is also known that regular exercise increase insulain sensitivity[8].

Figure 1: Illustrate the enhancement action of oxLDL during exercise and the elimination of cholesterol via HDL.[9]

Section 1.4 - AMPK and exercise:

The system that works as a key player in regulating energy balance is the AMPK (Activated Protein Kinase), so it is called energy sensor. Its activation is in response to ATP depletion (e.g. hypoxia) or to increase energy utilisation (e.g. exercise)[10].Once it activated it phosphorylate many substances that will lead to switch off ATP utilisation pathway such as fatty acid .AMPK also has along term effect, which is in alteration genes[10].

The mammalians AMPK is a serine /theronine kinase .The AMPK is composed of hetrotrimirec protein containing a catalytical α- subunit, an AMP-binding γ- subunit and a scaffolding β-subunit, which bind directly to α and γ- subunits[11].

There are 3 genes that encoding the γ subunits (γ1, γ2, γ3), and 2 genes encoding isoform of both α and β subunits (α1 , α2 ,β1and β2)[12, 13].

AMPK is activated by phosorylation of theronine 172(T-172) withen the loop of α-subunit. Many activate the phosolyration of T-172 but the most evidence up todate is the amplication of LKB1 and calcium[10].

The signalling pathway initiated by the activation of AMPK has an effect on lipid metabolism and glucose, also in gene expression and protein synthesis. These involves in some important regulating events in the liver, skeletal muscle, heart, adipose tissue, pancreas and the immune system[13].

'Physiological activation of AMPK occurs in skeletal muscles during exercise in response to increasing binding of AMP and decreased binding of ATP to the γ-subunit[13].'

As a result of a bout of exercise AMPK will be increased in the muscles that will effect the skeletal muscles glucose metabolism. Phosorylation of AMPK α Thr 172 is greater in Type II than type I[9].

During exercise the activation of AMPK in muscles, is thought to be responsible in increasing oxidation of fatty acid and glucose transport[13]. Coletta.A, et.al hypothesis that repetitive increases of AMPK in muscles during exercise, leads to increase glucose uptake, mitochondrial function and biogenesis[14]. In the acute bout of exercise it leads to significant increase of AMPK α2 activity in the skesletal muscles of diabetes people, that idea of increasing glucose disposal into skeletal muscle can lead to a strategy of the treatment of type 2 diabetes[14].Chen.Z said in his study in 2003,that AMPK α2 may be more actively coupled to glucose uptake than AMPK α1[15].

During exercise the isoform changes in AMPKα1and AMPK α2suggest that they play a physiological rol in skeletal muscle. Thus AMPK α1 is widely find in the body but AMPK α2 is found in muscles, heart and liver[16]. Also, there is another different that AMPKα1 is localised predominately in the cytosol but AMPK α2locoliized in both cytosol and nucleus. That's mean α2 isoform may have effect in gene regulation[16]

The physical activity of exercise by normal person increases activation of AMPK in skeletal muscles, liver and some other organs. Activation of AMPK during exercise in muscles cause in effect decreases binding ATP to the γ-subunit[13]. It also known that ADP is a product of ATP during exercise that will rapidly converted to AMP[13].

Fig 2: demonstrate that ATP converted to ADP during exercise. In turn ADP converted to AMP by adenylate kinase reaction[13].

Section 1.5 - PGC1α and exercise :

PGC1 α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) it is a transcription coactivater nuclear receptor. Its gene is located on chromosome 4 and it encoded for 798 amino acids in human [17].It is expressed in tissues such as Heart, skeletal muscle, liver and kidney. PGC1 α also expressed highly in brain and brown adipose tissues.The Transcription coactivater PGC1 α play a rule in gene regulation ,which a key regulator in energy metabolism.it is also involves in many biological responses such as mitochondrial biogenesis, glucose and fatty acid metabolism, adaptive thermogenesis , heart development and fiber type switching in muscles[14].

People with diabetes type 2 had reduced PGC1 genes excepression. Sriwijikamol.A, et.al2007 found in a study that PGC1 expression increased normally during exercise. Moderate exercise not only increases PGC1 but also increase gene excepration[14].

'AMPK phosorylated PGC1α directly both in vitro and cell. the activation of PGC1α via AMPK is important in gene regulator function in the muscles[18].

It has been reported byNarkar et al ,2008 ,that exercise increases mitochondrial activity and biogenesis within the skeletal muscles [19], that's mean exercise will also increase serum level of Reactive oxygen species (ROS). Which are produced by a product of mitochondrial consumption[20]. Moreover, ROS has an important effect in cellular function via activation of signalling cascade and upregulation of PGC1α in the muscles cells[20, 21].

It has been reported by Marry.L et,al. that there is evidence that ROS involves in glucose uptake signalling via AMPK pathway[22].

In 2010 Perry.C suggested that about of exercise regulate PGC1α mRNA abundance in human skeletal muscles[23] .PGC1α involves in asset of transcription cascade in skeletal muscles that regulates the response to exercise[24]. PGC1α often regulates the expression of a feed -forward switch in skeletal muscle fibre type. PGC1α dramatically increases PPAR α expression in various cell types and coactivates PPAR α to increase the rate of fatty acid oxidation[24] .Upregulation of PGC1α improves exercise performances greatly by increasing oxygen uptake.

Recently, it was suggested that prolong exercise increases PGC1 α protein for at least 24 hours[39] .A study has suggest that there is relationship between the function of PGC1 α and type 2 diabetes because, PGC1 α is essential in mitochondrial biogenesis and glucose / fatty acid metabolism [14]. There is evidence that type 2 diabetes people have low mitochondrial function and impaired oxygen uptake but a recent exercise reported by Liang.H ,et.al that the induction of PGC1 α in skeletal muscles is sufficient to increase mitochondrial function and oxygen uptake[25].

It has been suggested by Sriwijitkamol .A in 2007, that people with diabetes type 2 had reduced PGC1 gene excerption. In his study he found that PGC1 α expression increase normally during exercise[14]. Moderate exercise not only increases PGC1 α but also it will increase gene expression[14].

Section 1.6 - Peroxisome proliferator-activated receptors (PPARs):

This is a group of protein nuclear receptors, which controls cell transcription genes. It pays an important role in cell differential, development and metabolism such as lipids and proteins[26]. There are three isotopes of PPAR s: α (alpha), β/δ (beta/delta) and γ (gamma).PPAR α excerption is observed in brown fat, liver, kidney, muscles, heart and other tissues. PPAR β/δ (beta/delta) is expressed in brain, adipose tissue, and skin. Interestingly, PPAR β persistent expression was found in human placenta. PPAR γ expression has been noticed in white adipose tissue, intestinal mucosa (especially colon). It is also found in macrophages and skeletal muscles[26].

Figure 3: Illustrate the PPars types and where it found in the body .[27]

The PPARs, especially PPAR α and γ have implicated in several important metabolic disorders such as dyslipidaemia, diabetes and atherosclerosis. Its activity is modulated by drugs[26]. Fibrates which is a well known drug for hyperlipidemia are PPAR α ligands, it enhances the catabolism of triglyceride and it also reduces the production of VLDL[26]. Another drug is thiazolidinediones is PPAR γ ligands ,it is widely used for diabetes patient. TZD improves insulin sensitivity in patients with insulin resistant syndromes. There is strong evidence that PPAR γ is molecular target for antidiabetic drugs[28].

Section 1.7 - PPARs and exercise:

As a result of Narkar, V et.al study in 2008 exercise will increase AMPK phosophrolation in muscles which in role increases PGC1α and PPAR γ so many genes will be switch on[19]. As a result of that the percentage of body fat will be decreased, it will increase oxygen consumption and increases distance of exercise and the duration of running[19].

In a recent study result finding the effect of exercise in activating PPARγ to Th2 mediated cytokine signalling,reverse cholesterol transport and reduce glucose intolerance[29]. Yakeu et.al suggest that this may be potentially beneficial as anti-inflammatory, insulin sensitising and anti-atherogenic aspect of low intensity exercise[29].

Butcher .et, al. suggest that exercise increasing PPAR γ significantly[5]. There for it will up regulating target genes related to inflammation and pathophysiology of type 2 diabetes. Activation of PPAR γ by exercise enhances oxidative metabolism and mitochondrial biogenesis[5].

Section 1.8 - The Effects of Exercise on Various Aspects of Body Function:

As previously mentioned exercise phosorlyted AMPK in muscle that result in increased glucose uptake, parallel to its effect on glucose exercise or exercise mimetic increases fatty acid oxidation in skeletal muscles[19]. But exercise is not only affecting the genes in muscles but, it also affects other cells such as liver, adipose tissues, hypothalamus and blood cells[13].

Effects of exercise in liver and adipose tissues:

It has been approved that an acute bout of exercise has an effect in metabolic process of the liver and adipose tissues[13]. in liver and adipocyte exercise cause decrease in the energy states because of that, the AMPK/ATP ratio will be increased. Thus, the liver increases the glucose release to the circulation. According to Richter.E et,al 2009, activation of AMPK during exercise decreases the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase in the liver[13]. These two enzymes are related to gluconeogenic pathway. In the adipose tissues it will increase the hydrolysis of triglyceride and releases of nonesterified fatty acid in the circulation [13].

Effects of exercise on hypothalamus:

It has been understood that leptin decrease AMPK activity in hypothalamus. That is responsible in the ability of the hypothalamus to decrease food intake and increase sympathetic nervous system activity[13]. Richter.E et,al [13]reported according to another study by Flores et,al that exercise increase the ability of leptin and insulin that acts in the hypothalamus to decrease food intake. But how the exercise causes the effect still not knowen[13].

Effects of exercise on blood cells:

It has been appritated that exercise has an effect in increasing circulating blood cells. That activated proinflammatory gene response in leucocytes. As aresult of one study in 2008 by Azizk.S the exercise cuase substantial changes in gene exepresion in circulating neutrophils[30]. In the same study Azizk.S suggested that the genomic response in neutrophils was immediately after exercise and that suggest charctristic of cellular "wake-up call "[30] According to Connolly.P et,al that although neutrophils concentration are markedly increase in circulation during exercise but only lymphocytes and monocytes are responsible in gene regulation[31]. Bullne.P at,al found in 2006 that there is a downstream regulating effect of acute exercise in natural killer cells[32].Butcher.L et,al aggred that activation of PPARγ in monocytes leads to stimulates the activity of its regulate genes that in its role increases cellular uptake of lipids[5].

Physical activity such as exercise training known to have anti-inflammatory effect in monocytes [33]. Researchers find that patients with cardiovascular disease have elevated number of inflammatory monocytes percentage .

During exercise triggered inactivation of AMPK would have on monocellular function. As reported by Marsin .A et,al in 2002 that AMPK is phospholyrated in monocytes[34], while more recent work in UWIC has shown that monocyte AMPK activity can be affected by exercise [21].

Section 1.9 - The Effects of AMPK activators as Exercise Mimetics:

There are many drugs that can mimics exercise such as AICAR (aminoimidazole carboxamide ribonucleotide) and Oligomycin.

AICAR:

AICAR it is basically a drug that mimics exercise by activating AMPK. The administration of AICAR increases the expression of several key regulator genes. Narkar.V et,al 2008 said in his study that several global gene expression analyses of muscles discovered that when a treatment with AICAR alone upregulate about 32 genes that linked to oxidative metabolisms. In the same study he suggested that 30 of 32 genes are also regulated by PPAR[19]. Various in vivo studies has been using AICAR to activates AMPK that will directly phosolorylate PGC1α protein in Theronine-177 and serin-538.PGC1α coactivater by AMPK started a cascade of gene expression that controls many mitochondrial in skeletal muscles target genes. AICAR activates glucose uptake through a membrane of GLU 4(), it inhabits hepatic glucose. Also it suppresses insulin release from pancreatic cells. The effect of AICAR in the hypothalamus is to activate glucose responsive neurons, which in affect stimulate appetites. Adipose tissues are also affects with AICAR because; it inhabits glucose uptake and biolysis().

Figure 4a: domenstrate the effect of AICAR in some tissues.[35]

Figure 4b: shows AICAR chemical structure[36].

Richter.A et, al suggests that AICAR and metformin cause lowering of circulating glucose, so AICAR and metfomin may be beneficial in type 2 diabetes treatment[13]

AICAR causes the deplation of ATP that's in role activates AMPK to increase anaerobic respiration .

Jørgensen,S suggested that ACAR increases PGC1α by phosoloration of AMPK . Activation of AMPK by AICAR in muscles increases glucose transport and increase GLUT4 translocation at the plasma membrane [37].AICAR has been demonstrated to increase GLUT4 translocation in skeletal and heart muscles. It also increases fatty acid oxidation. Interestingly AMPK activation is sufficient to increase oxygen consumption and increase running endurance[40]

Oligomycin:

It is produce from streptomyces diastatochromogenes . oligomycins are a macrolide antibiotic it is used as oxidative phosphorylation inhibitor [41]. It inhabits membrane bound ATPase. It acts as a The addition of oligomycin to the tissues block the synthesis of ATP by preventing the movement of protons thought the ATP synthesis of mitochondria[41].

According to Marsin .A et,al that if oligomycin is incubated with activated monocytes thus, will activated AMPK that result in increasing glycolysis[34].

Section 1.10 - Project Aims/Hypothesis:

In this study our aim is to test the hypothesis that AMPK, when activated by exercise mimics (AICAR), enters a complex with PGC1α, and possibly with PPARγ, so changing gene expression in monocytes (THP-1 cells).

In these experiments, the monocytic THP-1 cells line will be used as an in vitro 'model system' for monocytes in vivo[41]. THP-1 cells were originally taken from a person with monocytic leukaemia, but for this study, cells will be obtained from The Health Protection Agency Culture Collections (Salisbury, UK). THP-1 is a promonocytic monocyte cell line derived from the peripheral blood of a 1 year old male with acute monocytic leukaemia. It is easly mature and differentiated to macrophages. THP-1 cells widely used in foam formation in atherosclerosis because this type of cells easily adheres to culture flask if treated with phorbol esters (PMA) or vitamin D3. Also,THP-1 cell can store more cholesterol ester than normal monocytes.

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